Phosphine-catalyzed [5+1] annulation of δ-sulfonamido-substituted enones with N-sulfonylimines: a facile synthesis of tetrahydropyridines

The first phosphine-catalyzed [5+1] annulation of enones with N-sulfonylimines works efficiently to give tetrahydropyridines.


Introduction
Phosphine-catalyzed annulation reactions are powerful synthetic tools to construct carbo-and heterocycles. 1 Since the pioneering work of Lu on phosphine catalysis, 2 many types of phosphine-promoted annulation reaction such as [1+n], 3 [2+n], 4 [3+n], 5 and [4+n] 6 annulations have been developed. In these reactions, the reactive intermediates from nucleophilic addition of phosphine to activated allenes, Morita-Baylis-Hillman carbonates, activated alkynes, etc., namely phosphorus ylides, serve as one-, two-, three-, or four-membered synthons when reacting with a variety of electrophilic coupling partners. Despite the fact that extremely diverse annulation reactions have been developed in the past two decades, 1 the development of phosphine catalysis is reaching its limit since phosphine catalysis is stuck with a single activation mode. Therefore, exploration of new activation modes and synthons is very signicant. Generally, phosphorus ylides work as equal to or less than four-membered synthons in phosphine catalysis. Examples with phosphorus ylides as greater than or equal to ve-membered synthons, which could probably be used for synthesis of six-membered or medium-ring cyclic compounds, have not been reported.
Functionalized tetrahydropyridines are important structural motifs of numerous biologically active natural products and synthetic pharmaceuticals, and their synthesis has attracted much attention. 7 In the area of phosphine catalysis, several attractive strategies involving phosphine-catalyzed annulation reactions have been established for the synthesis of functionalized tetrahydropyridines. In 2003, Kwon described PBu 3catalyzed [4+2] annulation of imines with allenes as a facile pathway to access functionalized tetrahydropyridines Scheme 1 Typical reactions involving phosphine catalysis to construct tetrahydropyridines.
(Scheme 1a). 8 Two years later, through the use of a bulky tertbutyl-substituted binaphthyl-based chiral phosphine as the catalyst, Fu accomplished asymmetric versions of the above [4+2] reactions with excellent enantioselectivities. 9 Aer the work of Kwon and Fu, Shi, 10a Marinetti 10b and Zhao 10c made great contributions to the development of this classic [4+2] annulation reaction, and the reaction was also utilized by Kwon as a key step in the synthesis of natural products. 11 In 2012, Loh and Zhong reported the phosphine-catalyzed asymmetric [2+4] annulation of olens with conjugate imines, which provided an alternative approach to the synthesis of enantioenriched tetrahydropyridines (Scheme 1b). 12 Aer the work, Chi, 13a Shi,13b Wu 13c and Zhang 13d enriched this reaction by introducing intramolecular modes or other types of catalysts. The [3+3] annulation mode is another typical way to synthesize functionalized tetrahydropyridines. In 2009, Kwon developed the rst phosphine-promoted [3+3] annulation of aziridines with allenoates to afford highly functionalized tetrahydropyridines under mild conditions, 14 broadening the synthetic strategies of tetrahydropyridines by utilizing different types of building block (Scheme 1c). Herein, as the initial attempt of our exploration of new ve-membered linear synthons for the [5+n] annulation reaction, we report a phosphine-catalyzed [5+1] annulation reaction of d-sulfonamido-substituted enones with N-sulfonylimines (Scheme 1d). To the best of our knowledge, this is the rst phosphine-catalyzed [5+1] annulation with a phosphorus ylide as a ve-membered synthon.

Results and discussion
At the outset of our experiment, the reaction between dsulfonamido-substituted enone 1a and N-sulfonylimine 2a was chosen as the model reaction, and various Lewis bases such as phosphines and amines were examined as the catalyst (Table 1). PPh 3 (20 mol%) did not show any catalytic activity, and no annulation product was observed aer the reaction mixture was stirred at rt for 72 h ( Table 1, entry 1). Under otherwise identical conditions, the [5+1] annulation product 3aa was obtained in 20% yield when MePPh 2 was employed as the catalyst (entry 2). It seems that more nucleophilic phosphines were benecial to the reaction. With the use of Me 2 PPh as the catalyst, the reaction worked at rt for 36 h to give the product 3aa in 75% yield (entry 3). Compared with Me 2 PPh, more nucleophilic Bu 3 P displayed much better catalytic activity, greatly shortening the reaction time to 3 h to afford the product 3aa in 95% yield (entry 4). Lowering the catalyst loading to 10 mol% still resulted in the product in 90% yield, albeit requiring a reaction time of 28 h (entry 5). However, when the catalyst loading was lowered to 5 mol%, the yield of 3aa was greatly decreased to 15% (entry 6). With the use of organic amines such as Et 3 N, DMAP and DABCO instead of phosphines as the catalyst, no annulation product was observed even when the reaction time was prolonged to 72 h under otherwise identical conditions (entries 7-9). A stronger Lewis base DBU displayed certain catalytic activity, promoting the reaction to afford the annulation product 3aa in 20% yield (entry 10).
Aer the optimal conditions were determined, various Nsulfonylimines with different substituents were carefully investigated ( Table 2). The results indicated that imines with either electron-decient or electron-rich substituents on the  benzene ring are suitable substrates, and the corresponding 1,2,3,6-tetrahydropyridine derivatives were obtained with usually good to high yields. However, the position of the substituent on the benzene ring had a remarkable inuence on the reaction. For example, the 2-Cl, 2-Br, and 2-Me substituted aryl imines led to lower yields of the products compared with their 3-or 4-substituted counterparts (entry 5 vs. entries 6-7, entry 8 vs. entries 9-10, entry 11 vs. entries 12-13). The 2-thiophenyl and 2-naphthyl imines were also compatible substrates under the optimal reaction conditions and the corresponding products were obtained in excellent yields (entries 16-17). The N-Boc-3-indole derived imine 2r also underwent the reaction, providing the product 3ar in 72% yield (entry 18). Unfortunately, the alkyl N-sulfonylimine 2s did not perform the reaction and no desired product was observed (entry 19). The structure of the [5+1] annulation product was unambiguously determined through X-ray crystallographic analysis of the product 3aq. 15 As shown in Table 3, a series of functionalized ketones with variations of the R group were examined under the optimal reaction conditions. The results showed that no matter what the electronic properties or the substitution positions of the substituents, such as F-, Cl-, Br-, Me-, MeO-, and -NO 2 substituted enones at the benzene ring, the reactions proceeded smoothly to afford the desired 1,2,3,6-tetrahydropyridine derivatives with good to excellent yields (entries 1-12). However, the MeO and NO 2 substituted substrates required longer times to nish the reaction (entries 10-12). In addition, the 2-thiophenyl and 2-naphthyl modied enones underwent the [5+1] annulation reaction to produce the corresponding products in excellent yields (entries 13-14). To our delight, aliphatic enone 1s underwent this reaction to afford the desired product 3sa in 73% yield (entry 15).
Following the substrate scope evaluation, we attempted to gure out how the reaction works. As a result, several control experiments were carried out under the optimal reaction conditions (Scheme 2). In the presence of PBu 3 , treatment of enone 1a with N-sulfonylimine 2t afforded the annulation product 3aa in 96% yield together with benzenesulfonamide. In contrast, treatment of enone 1p with imine 2a afforded the annulation product 3pa in 94% yield together with p-toluenesulfonamide. By comparison, d-Boc-amido-substituted enones did not undergo annulation in the presence of phosphine. Meanwhile, when the benzoyl group was replaced by an ester group, the reaction did not work either. Therefore, the acidity of the substituted amine group at the d-position of the ketone probably has a remarkable impact on the reaction process, and so does the benzoyl group. Replacement of the imine substrate with benzaldehyde did not yield the desired annulation product (Scheme 2). These results demonstrated that the amino-group in the annulation product comes from the enone substrate.
On the basis of the results obtained, a plausible mechanism was proposed (Scheme 3). 1 Nucleophilic addition of the phosphine catalyst to enone 1a produces a zwitterionic intermediate Subsequent intramolecular nucleophilic addition furnishes annulation to form the intermediate VI, which regenerates the phosphine catalyst to give the nal annulation product 3aa.
As indicated in Scheme 4, a gram-scale preparation of the product 3aa was carried out. 1.02 g of enone 1a (3.1 mmol) reacted with N-sulfonylimine 2a (1.22 g, 4.7 mmol) under the optimal reaction conditions to give 1,2,3,6-tetrahydropyridine derivative 3aa in 85% yield. Treatment of 3aa with 4- methylbenzenethiol and K 2 CO 3 in air provided a good yield of the pyridine derivative 4 via dehydrogenation aromatization. Further exploration on the variety of the sulfonamidosubstituted enone indicated that enone 5, which is a homologue of enone 1a, could work as a C4 synthon to perform the [4+1] annulation reaction to give 2,5-dihydro-1H-pyrrole derivative 6 in 23% yield (Scheme 4). As shown in Scheme 5, the asymmetric version of the reaction was also investigated. To our delight, with the use of chiral phosphine P1 as the catalyst and CF 3 Ph as the solvent, the [5+1] annulation of enone 1a with N-sulfonylimine 2a worked at À10 C for 65 h to give chiral product 3aa in 28% yield with up to 73% ee. When we decreased the amount of P1 to 10 mol%, the reaction worked at rt to give the product in 29% yield and 71% ee, which is similar to the result from the reaction using 20 mol% of the catalyst at low temperature. With the use of chiral phosphines P2 or P3 as the catalyst, moderate enantiomeric excesses were obtained. Unfortunately, a variety of attempts to improve enantioselectivity failed.

Conclusions
In summary, we have developed a phosphine-catalyzed [5+1] annulation of d-sulfonamido-substituted enones with N-sulfonimines to prepare tetrahydropyridines with good to excellent yields. The reaction has broad substrate scope for both enones and N-sulfonimines. A plausible mechanism was proposed according to the results of control experiments. In addition, the reaction on the gram-scale worked well and further transformation of the product provided the pyridine derivative. The asymmetric version of the model [5+1] annulation reaction was also investigated, and up to 73% ee was achieved.

Conflicts of interest
There are no conicts to declare.